神经肌肉阻断剂

CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Division of Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia HISTORY OF NEUROMUSCULAR BLOCKING AGENTS AND CLINICAL DEVELOPMENT HISTORY 1494 - Tales of travelers killed by poison darts 1551 - Ourari” or “cururu” meaning “bird killer” 1812 - Curarized cat kept alive by artificial respiration 1912 - Curare used to prevent fractures during ECT 1941 - Initial use by Griffith, Culler, and Rovenstine 1951 - Succinylcholine chloride first used in Stockholm INTRODUCTION OF NEW DRUGS 1494 - 1942 Curare 1947 - 1951 Succinylcholine chloride, Gallamine, Metocurine, Decamethonium 1960s Alcuronium 1970s Pancuronium bromide, Fazadinium 1980s Vecuronium bromide, Atracurium besylate 1990 Pipecuronium bromide 1991 Doxacurium chloride 1992 Mivacurium chloride 1994 Rocuronium bromide 1999 Rapacuronium bromide STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide Naturally occurring benzylisoquinolines: curare, metocurine Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride THE IDEAL RELAXANT Nondepolarizing Rapid onset Dose-dependent duration No side-effects Elimination independent of organ function No active or toxic metabolites ONSET OF PARALYSIS IS AFFECTED BY: Dose (relative to ED95) Potency (number of molecules) Keo (chemistry/blood flow) Clearance Age Neuromuscular Blocking Agents and Patient Evaluation Assessing Postoperative Neuromuscular Function WSustained 5-second head lift WAbility to appose incisors (clench teeth) WNegative inspiratory force 40 cm H2O WAbility to open eyes wide for 5 seconds WHand-grip strength WSustained arm/leg lift WQuality of speaking voice WTongue protrusion Assessing Postoperative Neuromuscular Function CLINICAL ASSESSMENT Kopman AF, et al. Anesthesiology, 1997:86;765 Ali HH, et al. Br J Anaesth. 1975;47:570 Assessing Postoperative Neuromuscular Function Train-of-Four (TOF) Fade Ratio 9997100100% 959110090% 948810080% 92829770%* 95709160% 100100100Control =100 Peak Exp. Flow Rate Inspiratory ForceVital CapacityTOF Ratio Assessing Postoperative Neuromuscular Function Ali HH, et al. Br J Anaesth. 1975;47:570 THE ORIGIN OF THE GOLD STANDARD * Historically regarded as the Gold Standard NEW DATA SUGGEST THAT A TOF OF 0.90 MAY BE NEEDED TO ENSURE NORMAL FUNCTION Assessing Postoperative Neuromuscular Function WKopman: A TOF 0.90 compatible with normal clinical tests (Anesthesiology. 1997;86:765) WEriksson: Pharyngeal function normal at TOF 0.90 (Anesthesiology. 1997;87:1035) Assessing Postoperative Neuromuscular Function WPatients are often returned to the PACU with residual paralysis1 WThe TOF ratio of 0.70 may be inadequate for discharge of an ambulatory patient1 WTOF ratios 0.40 are difficult to assess clinically2 ASSESSING TOF FADE RATIO 1Viby-Mogensen J, et al. Anesthesiology. 1979;50:539 2Kopman AF, et al. Anesthesiology. 1994;81:1394 Assessing Postoperative Neuromuscular Function WRecovery is inadequate if fade is detected1,2 WClinical trials are needed to demonstrate measurement techniques for TOF ratios of 0.902 1Eriksson, LI, et al. Anesthesiology. 1997;87:1035 2Bevan, DR, et al. Anesthesiology. 1988;69:272 TOF FADE RATIO: CONCLUSION W Vagolytic WPartially block cardiac muscarinic receptors involved in heart rate slowing, resulting in increased heart rate: Wrapacuronium pancuronium rocuronium vecuronium W Generally do not promote histamine release WException: rapacuronium W Organ-dependent elimination WKidneys and liver Neuromuscular Blockers: Chemical Structure 52 Suppl 1:3SDurant NN, et al. J Pharm Pharmacol. 1979:31(12):831 Marshall IG, et al. Br J Anaesth. 1980;52 Suppl 1:11S WAbsence of vagolytic effect Wthese drugs do not block cardiac-vagal (muscarinic) receptors WHistamine release WdTc atracurium mivacurium cisatracurium Wcan cause rare bronchospasm, decreased blood pressure, increase of heart rate WGenerally organ-independent elimination1 Wesp: atracurium, cisatracurium, mivacurium WNoncumulative2 Neuromuscular Blockers: Chemical Structure 55;3S 2Ali HH, et al. Br J Anaesth. 1983;55:107S Ultra- Short Short Clinical duration (injection to T25) 6 - 8 12 - 20 30 - 45 60 30 succinyl- choline mivacurium cisatracurium doxacurium Assumes bolus dose = 2x ED95 1Anectine (succinylcholine chloride) Package Insert 2Mivacron (mivacurium chloride) Package Insert 3Nimbex (cisatracurium besylate) Package Insert 4Nuromax (doxacurium chloride) Package Insert 1 2 3 4 DURATION OF ACTION OF NEUROMUSCULAR BLOCKING AGENTS Ultra-Short: Succinylcholine chloride Short: Mivacurium chloride Intermediate: Rocuronium bromide, Vecuronium bromide, Atracurium besylate Long: Pancuronium bromide, curare, metocurine, Pipecuronium bromide, Doxacurium chloride CARDIOVASCULAR PROFILE OF NEUROMUSCULAR BLOCKING AGENTS Hemodynamics, histamine release, and other aspects HISTAMINE RELEASING POTENTIAL Significant Insignificant Tubocurarine+ + + Rocuronium bromide Metocurine + Vecuronium bromide Atracurium besylate + Pancuronium bromide Mivacurium chloride + Pipecuronium bromide Succinylcholine chloride + Doxacurium chloride Muscle Relaxants Pancuronium Vagolytic: increases heart rate, may require beta blockade Easy to use Intermediate duration of action Slower onset Not reversed at end of case Muscle Relaxants Vecuronium No effects on HR, BP Requires reconstitution Reliable and controllable duration of action Slower onset Stable hemodynamics/no histamine release Muscle Relaxants Rocuronium No effects on HR, BP Easy to use, liquid, no refrigeration Reliable and controllable duration of action Fast onset Stable hemodynamics/no histamine release Effects of Rocuronium on Heart Rate Time (minutes) 100 90 80 70 60 50 40 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Heart Rate (beats/min) Levy et al. Anesth Analg 1994;78,318-321. 600 mcg/kg 900 mcg/kg 1200 mcg/kg Effects of Rocuronium on Mean Arterial Pressure Time (minutes) 100 90 80 70 60 50 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Mean Arterial Pressure (mmHg) 600 mcg/kg 900 mcg/kg 1200 mcg/kg Levy et al. Anesth Analg 1994;78,318-321. Effects of Rocuronium on Histamine Release Time (minutes) 0.0 1.0 2.0 3.0 4.0 5.0 Plasma Histamine ( ng /ml) Levy et al. Anesth Analg 1994;78,318-321. 600 mcg/kg 900 mcg/kg 1200 mcg/kg 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Muscle Relaxants Rapacuronium Minimal effects on HR, BP Controllable duration of action Fast onset Stable hemodynamics/minimal histamine release Potential for bronchospasm led to its removal in 2001 COSTS OF NEUROMUSCULAR BLOCKING AGENTS AND SELECTION CRITERIA W Cost of care acquisition cost W The real, substantial savings accrue from use of intermediate- and short-acting drugs because: